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Though once the main treatment for anxiety disorders—often as monotherapy1—benzodiazepines are now primarily used as adjunctive agents.2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.
While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,4 clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.5,6 They may cause memory impairment7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.9-11 Benzodiazepines also have been associated with falls and fractures,12 and worse outcomes in patients with posttraumatic stress disorder.13 Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,14 though others found that was not always the case.15 Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.16 Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.17
Despite the potential for adverse effects, benzodiazepine use remains common.18 These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.19 Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”19 Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.
This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzodiazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table20).
Benzodiazepine pharmacodynamics
Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits22 and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.24 BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.24
Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.25 Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)26 and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).27
From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,28 although they generally appear effective for immediate use to treat anxiety in acute settings.29 The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.30 D
Continue to: Pharmacology and clinical effects
Pharmacology and clinical effects
Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.31 In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.
Absorption
Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.32 Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.33 Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 134); the fat content of the meal appears important in moderating this effect.35 The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.
CNS penetration
Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.
Lipophilicity and duration of effect
Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.
By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.36 Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al36 found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.
Continue to: Metabolism
Metabolism
Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines39 and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other nongenetic factors.
Drug-drug interactions
Apart from lorazepam,40,41 oxazepam,42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 220).39 As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines44; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.31 The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,45 but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.46 For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.47 The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,48 the clearance of oxidatively metabolized benzodiazepines is reduced.49 Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al50 found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.51
Hepatic disease
Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.40
Aging and benzodiazepine metabolism/clearance
Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).
Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.52 In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”52 Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”52 These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.40 Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.
Continue to: Obesity
Obesity
The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.55,56
Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.57 Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.58 However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In
How quickly do benzodiazepines work?
Benzodiazepines act quickly. Meta-analyses36 suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 336). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psychotherapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.
What is the ‘best’ dose?
As seen with other classes of psychotropic medications,4 the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).36 A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.49 As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.62 This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.63 As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.
Which benzodiazepine should I prescribe?
Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al36 that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 436).
Continue to: Another aspect of the superiority...
Another aspect of the superiority of clonazepam in some research relates to its pharmacokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.64 While it is difficult to assess this in clinical trials, Herman et al65 provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.
Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.
Practical considerations
When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.
Patients age <18 are unlikely to have full expression of GABA receptors in the brain30 and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzodiazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzodiazepines is also accelerated, potentially decreasing half-life by up to 50%.
When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.
Continue to: The properties of individual benzodiazepines...
The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.
Bottom Line
The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.
Related Resources
- Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
- Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.
Drug Brand Names
Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan
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41. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6(2):89-105. doi:10.2165/00003088-198106020-00001
42. Walkenstein SS, Wiser R, Gudmundsen CH, et al. Absorption, metabolism, and excretion of oxazepam and its succinate half‐ester. J Pharm Sci. 1964;53(10):1181-1186. doi:10.1002/jps.2600531010
43. Shull HJ, Wilkinson GR, Johnson R, et al. Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med. 1976;84(4):420-425. doi:10.7326/0003-4819-84-4-420
44. Abernethy DR, Greenblatt DJ, Ochs HR, et al. Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther. 1983;33(5):628-632. doi:10.1038/clpt.1983.85
45. Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther. 1980;27(3):301-312. doi:10.1038/clpt.1980.40
46. Ochs HR, Greenblatt DJ, Knüchel M. Kinetics of diazepam, midazolam, and lorazepam, in cigarette smokers. Chest. 1985;87(2):223-226. doi:10.1378/chest.87.2.223
47. Smith RB, Gwilt PR, Wright CE 3rd. Single- and multiple-dose pharmacokinetics of oral alprazolam in healthy smoking and nonsmoking men. Clin Pharm. 1983;2(2):139-143.
48. Figgitt DP, McClellan KJ. Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders. Drugs. 2000;60(4):925-954. doi:10.2165/00003495-200060040-00006
49. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993;24(6):453-471. doi:10.2165/00003088-199324060-00003
50. Yasui N, Kondo T, Furukori H, et al. Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology (Berl). 2000;150(2):185-190. doi:10.1007/s002130000438
51. Özdemir M, Aktan Y, Boydagˇ BS, et al. Interaction between grapefruit juice and diazepam in humans. Eur J Drug Metab Pharmacokinet. 1998;23(1):55-59. doi:10.1007/BF03189827
52. Greenblatt DJ, Harmatz JS, Zhang Q, et al. Slow accumulation and elimination of diazepam and its active metabolite with extended treatment in the elderly. J Clin Pharmacol. 2021;61(2):193-203. doi:10.1002/jcph.1726
53. Abernethy DR, Greenblatt DJ. Drug disposition in obese humans: an update. Clin Pharmacokinet. 1986;11(3):199-213. doi:10.2165/00003088-198611030-00002
54. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71-87. doi:10.2165/11318100-000000000-00000
55. Bauer LA. Drug Dosing in special populations: renal and hepatic disease, dialysis, heart failure, obesity, and drug interactions. In: Weitz M, Thomas, CM, eds. Applied Clinical Pharmacokinetics. 3rd ed. McGraw-Hill Education; 2014. https://accesspharmacy.mhmedical.com/book.aspx?bookid=1374
56. Kendrick JG, Carr RR, Ensom MHH. Pharmacokinetics and drug dosing in obese children. J Pediatr Pharmacol Ther. 2010;15(2):94-109. doi:10.5863/1551-6776-15.2.94
57. Brill MJE, Diepstraten J, van Rongen A, et al. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51(5):277-304. doi:10.2165/11599410-000000000-00000
58. Derry CL, Kroboth PD, Pittenger AL, et al. Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men. J Clin Psychopharmacol. 1995;15(3):197-205. doi:10.1097/00004714-199506000-00008
59. Abernethy DR, Greenblatt DJ, Divoll M, et al. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet. 1984;9(2):177-183. doi:10.2165/00003088-198409020-00005
60. Abernethy DR, Greenblatt DJ, Divoll M, et al. Prolonged accumulation of diazepam in obesity. J Clin Pharmacol. 1983;23(8-9):369-376. doi:10.1002/j.1552-4604.1983.tb02750.x
61. Abernethy DR, Greenblatt DJ, Divoll M, et al. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873-880.
62. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry. 1993;54 Suppl:4-11.
63. Chen YT, Liu CY, Chang CM, et al. Perceptions, clinical characteristics, and other factors associated with prolonged and high daily dose of benzodiazepine use among patients with anxiety or depressive disorders. J Affect Disord. 2020;271:215-223. doi:10.1016/j.jad.2020.03.077
64. Herman JB, Brotman AW, Rosenbaum JF. Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry. 1987;48(Suppl):22-28.
65. Herman JB, Rosenbaum JF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol. 1987;7(3):175-178.
Though once the main treatment for anxiety disorders—often as monotherapy1—benzodiazepines are now primarily used as adjunctive agents.2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.
While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,4 clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.5,6 They may cause memory impairment7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.9-11 Benzodiazepines also have been associated with falls and fractures,12 and worse outcomes in patients with posttraumatic stress disorder.13 Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,14 though others found that was not always the case.15 Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.16 Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.17
Despite the potential for adverse effects, benzodiazepine use remains common.18 These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.19 Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”19 Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.
This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzodiazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table20).
Benzodiazepine pharmacodynamics
Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits22 and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.24 BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.24
Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.25 Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)26 and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).27
From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,28 although they generally appear effective for immediate use to treat anxiety in acute settings.29 The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.30 D
Continue to: Pharmacology and clinical effects
Pharmacology and clinical effects
Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.31 In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.
Absorption
Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.32 Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.33 Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 134); the fat content of the meal appears important in moderating this effect.35 The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.
CNS penetration
Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.
Lipophilicity and duration of effect
Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.
By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.36 Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al36 found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.
Continue to: Metabolism
Metabolism
Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines39 and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other nongenetic factors.
Drug-drug interactions
Apart from lorazepam,40,41 oxazepam,42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 220).39 As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines44; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.31 The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,45 but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.46 For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.47 The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,48 the clearance of oxidatively metabolized benzodiazepines is reduced.49 Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al50 found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.51
Hepatic disease
Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.40
Aging and benzodiazepine metabolism/clearance
Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).
Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.52 In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”52 Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”52 These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.40 Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.
Continue to: Obesity
Obesity
The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.55,56
Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.57 Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.58 However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In
How quickly do benzodiazepines work?
Benzodiazepines act quickly. Meta-analyses36 suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 336). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psychotherapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.
What is the ‘best’ dose?
As seen with other classes of psychotropic medications,4 the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).36 A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.49 As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.62 This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.63 As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.
Which benzodiazepine should I prescribe?
Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al36 that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 436).
Continue to: Another aspect of the superiority...
Another aspect of the superiority of clonazepam in some research relates to its pharmacokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.64 While it is difficult to assess this in clinical trials, Herman et al65 provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.
Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.
Practical considerations
When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.
Patients age <18 are unlikely to have full expression of GABA receptors in the brain30 and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzodiazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzodiazepines is also accelerated, potentially decreasing half-life by up to 50%.
When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.
Continue to: The properties of individual benzodiazepines...
The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.
Bottom Line
The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.
Related Resources
- Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
- Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.
Drug Brand Names
Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan
Though once the main treatment for anxiety disorders—often as monotherapy1—benzodiazepines are now primarily used as adjunctive agents.2-4 Their ability to produce rapid anxiolysis represents a significant therapeutic advantage, but in recent decades their tolerability, class-specific risks, and lack of antidepressant properties contributed to benzodiazepines being largely replaced by selective serotonin reuptake inhibitors (SSRIs) for the pharmacologic treatment of anxiety. This shift within the pharmacologic armamentarium has decreased many clinicians’ familiarity with benzodiazepines.
While benzodiazepines continue to have an important role in managing anxiety disorders, particularly treatment-resistant anxiety,4 clinicians must consider the limitations of these agents. Benzodiazepines can be associated with abuse and dependence, and overdose risk when combined with opiates.5,6 They may cause memory impairment7,8 and conflicting data suggest they may contribute to the risk of developing cognitive disorders.9-11 Benzodiazepines also have been associated with falls and fractures,12 and worse outcomes in patients with posttraumatic stress disorder.13 Some studies of patients with chronic obstructive pulmonary disease (COPD) found benzodiazepines may increase the risk of COPD exacerbations and accidental overdose,14 though others found that was not always the case.15 Benzodiazepines may be associated with an increased risk of spontaneous abortion when used early in pregnancy.16 Prospective research in women who were breastfeeding found benzodiazepines may cause sedation in up to 2% of infants.17
Despite the potential for adverse effects, benzodiazepine use remains common.18 These medications have a rapid onset of action, are useful for breakthrough symptoms, may enhance treatment adherence, and alleviate activating symptoms of SSRIs. Like other commonly used medications, benzodiazepines have the potential for both harm and benefit.19 Similar to other medications with tolerability concerns but established efficacy, particularly in treatment-resistant anxiety disorders, it is important to balance “overprescribing … to patients at risk and underusing these effective medications when indicated.”19 Though the use of benzodiazepines has been discouraged and perceptions have shifted, knowledge of benzodiazepines and benzodiazepine pharmacology also has been degraded contemporaneously.
This article provides a synthesis of the clinically relevant pharmacology of benzodiazepines, with a focus on orally administered benzodiazepines, which are more common in outpatient clinical practice. Specifically, this review describes the pharmacology of benzodiazepines, benzodiazepine medication interactions, the relationship between pharmacologic characteristics and treatment response/tolerability, and selection and dosing of oral benzodiazepines (Table20).
Benzodiazepine pharmacodynamics
Benzodiazepines act at the gamma-aminobutyric acid (GABA)-A receptor complex and bind allosterically.21-23 Comprised of 5 glycoprotein subunits (2 alpha subunits, 2 beta subunits, and 1 gamma subunit), the receptor has 2 distinct sites at which the endogenous inhibitory transmitter GABA binds and 1 benzodiazepine binding site. Benzodiazepines bind within a socket created by the alpha and gamma subunits22 and after binding induce a conformational change in the receptor, which enhances GABA binding. There are 2 types of benzodiazepine receptors: BZ1 and BZ2. The subunits play a critical role in driving the pharmacologic characteristics of the receptor.24 BZ1 and BZ2 receptors bind benzodiazepines, although they are differentially distributed within the brain. Binding at BZ1 receptors—which are distributed in cortical, thalamic, and cerebellar regions—contributes to sedation and deleterious effects of benzodiazepines on memory (eg, anterograde amnesia). BZ2 receptors (which contain gamma-2 subunits) are responsible for anxiolytic and muscle-relaxing effects. They are distributed throughout limbic regions and motor tracts, including motor neurons and neurons in the dorsal horn of the spinal cord.24
Benzodiazepines—positive GABA-A receptor allosteric modulators—produce phasic inhibition, largely through the alpha and gamma subunits discussed above. In contrast, newer positive allosteric modulators (eg, zuranolone) bind at the alpha/beta subunits.25 Mechanistically, endogenous neuroactive steroids and nonbenzodiazepine GABA-A–positive allosteric modulators such as zuranolone and ganaxolone also differ in their regulation of GABA-A (downregulated with benzodiazepines and hypothetically upregulated with zuranolone)26 and their synaptic effects (benzodiazepines synaptically vs endogenous neurosteroids and nonbenzodiazpine positive allosteric modulators extrasynaptically).27
From a developmental perspective, benzodiazepines may have less efficacy for anxiolysis and worse tolerability in some pediatric patients,28 although they generally appear effective for immediate use to treat anxiety in acute settings.29 The differences in efficacy and tolerability may be related to pharmacodynamic differences between pediatric populations and adults. GABA receptor expression and function do not reach adult levels until age 14 to 17½ for subcortical regions and age 18 to 22 for cortical regions, although girls reach adult expression of GABA receptors slightly earlier than boys.30 D
Continue to: Pharmacology and clinical effects
Pharmacology and clinical effects
Benzodiazepine pharmacokinetics are intimately linked with the onset of action and duration of clinical effect and vary based on the route of administration, absorption, and distribution/redistribution.31 In this review, we focus on oral administration as opposed to IV, IM, sublingual, or intranasal administration.
Absorption
Benzodiazepines are rapidly absorbed after oral administration and quickly enter the systemic circulation. However, absorption rates vary depending on specific aspects of the gastrointestinal milieu and intrinsic properties of the benzodiazepine. For example, alprazolam is more rapidly absorbed than most other benzodiazepines, with a Tmax of 1.8 hours compared to lorazepam, which has a Tmax of approximately 2 hours. These pharmacokinetic effects instantiate differences in tolerability and efficacy. Thus, following single doses of alprazolam and diazepam, self-rated sedating effects and impairment on a task of working memory suggest that effects have a more rapid onset for alprazolam relative to lorazepam.32 Food and concomitant medications can significantly affect benzodiazepine absorption. A single-dose, 3-way crossover study demonstrated that taking diazepam concomitantly with an antacid (eg, aluminum hydroxide) decreased peak concentrations and prolonged absorption by approximately 30 minutes. However, total absorption of the medication was unaffected.33 Additionally, administration of diazepam with food significantly slows absorption from 1 hour 15 minutes to approximately 2 hours 30 minutes and increases benzodiazepine absorption by 25% (Figure 134); the fat content of the meal appears important in moderating this effect.35 The impact of food on alprazolam varies by formulation. For example, when administered in an extended-release (XR) formulation with a high-fat meal, alprazolam absorption increases by one-third, while absorption for administration of the orally disintegrating tablet with a high-fat meal increases from 1 hour 30 minutes to 2 hours. Similarly, for lorazepam, administration with a meal delays absorption by approximately 2 hours; however, this effect does not appear present with the XR formulation. Administering benzodiazepines with food can be clinically leveraged to either accelerate the onset of action or decrease peak-associated adverse effects. Thus, when a highly lipophilic benzodiazepine is needed to treat acute anxiety or prior to an expected anxiogenic stimuli, administering the medication without food may produce a faster onset of action.
CNS penetration
Benzodiazepines enter the CNS by passive diffusion. Because of this, lipophilicity at physiologic pH influences the rate at which a benzodiazepine crosses the blood-brain barrier. The rate at which benzodiazepines enter the CNS influences their clinical effects and the speed at which both efficacy (ie, anxiolysis) and adverse effects (ie, sedation, slowed cognition) are observed. In general, more lipophilic medications initiate their anxiolytic effect more quickly. However, by quickly leaving the CNS (through the same mechanism that allowed them to enter the CNS at such speed), their effects rapidly cease as they redistribute into fat. Thus, highly lipophilic benzodiazepines produce more intense effects compared to less lipophilic benzodiazepines. For these reasons, lipophilicity is more important than half-life for determining the duration of effect in most patients.
Lipophilicity and duration of effect
Benzodiazepines and their metabolites tend to be highly protein-bound and distributed in fat- and lipid-enriched areas such as the CNS. As a result, the more lipophilic agents generally have the highest rates of absorption and the fastest onset of clinical effects. The duration of action for many benzodiazepines is determined by the rate and extent of distribution (a function of lipophilicity) rather than by the rate of elimination. For example, diazepam has a longer half-life than lorazepam, but its duration of action following a single dose is shorter. This is because diazepam is more lipophilic and therefore more extensively distributed (particularly to adipose tissue). This results in it leaving the brain and blood and distributing to other tissues. In turn, its CNS effect (ie, anxiolytic effects) are more quickly terminated.
By contrast, less lipophilic benzodiazepines maintain their CNS concentrations longer; they have a longer duration of action because of their slower redistribution, which culminates in a shorter half-life, and are less extensively distributed to peripheral tissues. In essence, this means that (other things being equal) a less lipophilic benzodiazepine produces a more sustained anxiolytic effect compared to a highly lipophilic benzodiazepine.36 Lipophilicity is also important in predicting some cognitive adverse effects, including amnesia. Benzodiazepines with high lipophilicity have greater absorption and faster onset of action as well as more rapid amnestic effects.37,38 These effects may relate to overall efficacy differences for oral benzodiazepines. A recent meta-analysis by Stimpfl et al36 found that less lipophilic benzodiazepines produced a greater response compared to more lipophilic benzodiazepines.
Continue to: Metabolism
Metabolism
Regarding cytochrome P450 (CYP) metabolism, polymorphic CYP2C19 and CYP3A4/5 are involved in the metabolism of several benzodiazepines39 and CYP2B6 has been recognized as a contributor to diazepam metabolism. CYP3A5 gene polymorphisms may produce variation in alprazolam metabolism; however, the predominant cytochrome involved in the metabolism of oxidatively metabolized benzodiazepines (ie, benzodiazepines other than lorazepam, oxazepam, and temazepam) is primarily CYP3A4, and most effects on CYP3A4 activity are related to concomitant medications and other nongenetic factors.
Drug-drug interactions
Apart from lorazepam,40,41 oxazepam,42,43 and temazepam, most benzodiazepines are metabolized through oxidative mechanisms that involve CYP3A4 (Figure 220).39 As such, their metabolism is influenced by medications that impact CYP3A4, including antifungals (eg, ketoconazole), calcium channel blockers (eg, verapamil, diltiazem), nefazodone, some protease inhibitors, and macrolide antibiotics. Research has examined the impact of low-dose estrogen oral contraceptives (OCPs) on exposure (eg, plasma concentrations) of several benzodiazepines. The mechanism for this interaction is likely complex and putatively involves multiple pathways, including inhibition of CYP3A4 by OCPs. The effects of OCPs on benzodiazepine pharmacokinetics vary based on the metabolism of the benzodiazepine. In general, medications oxidized and nitroreduced (eg, chlordiazepoxide, alprazolam, diazepam, and nitrazepam) have decreased clearance in patients treated with OCPs. Regarding nonoxidatively metabolized benzodiazepines, data are mixed. Research found no OCP-related effects on the pharmacokinetics of nonoxidatively metabolized benzodiazepines44; another study suggested that clearance of these medications—through increased glucuronidation—may be increased.31 The effect of smoking on benzodiazepine concentration has been well documented. Smoking increases the clearance of orally administered diazepam,45 but not IV diazepam, midazolam, or lorazepam, suggesting that this represents a first-pass effect.46 For alprazolam, plasma concentrations are reduced by 15% to 30% in smokers and total body clearance is 24% greater compared to nonsmokers, which results in an approximately 50% increase in half-life in nonsmokers compared to smokers.47 The most notable interaction between benzodiazepines and SSRIs is seen with fluvoxamine. Because fluvoxamine moderately inhibits CYP2C19 and CYP3A4 and potently inhibits CYP1A2,48 the clearance of oxidatively metabolized benzodiazepines is reduced.49 Additionally, the effects of grapefruit juice—a potent inhibitor of CYP3A4—has been evaluated for several benzodiazepines. Yasui et al50 found grapefruit juice did not alter alprazolam plasma concentrations. However, in separate research, grapefruit juice tripled diazepam exposure, increased peak concentrations 1.5-fold, and prolonged absorption.51
Hepatic disease
Exposure to benzodiazepines—other than lorazepam, oxazepam, and temazepam—is influenced by intrinsic hepatic disease and requires dose adjustment in individuals with significant hepatic impairment. The impact of hepatic disease on the clinical pharmacology of benzodiazepines may relate to 2 factors: protein binding and metabolism. In a study of individuals with cirrhosis, lorazepam binding was decreased, although its metabolism and clearance were largely unaffected.40
Aging and benzodiazepine metabolism/clearance
Aging is associated with myriad physiologic changes (eg, decrease in renal clearance after age 40, changes in body fat distribution, changes in activity of cytochromes) that are relevant to benzodiazepine pharmacology. They may underlie differences in the tolerability of benzodiazepines and other clinically relevant characteristics (eg, duration of action, accumulation).
Several studies have evaluated the impact of aging on the clearance and disposition of selected benzodiazepines. The respective half-lives of chlordiazepoxide and diazepam increase from 4- to 6-fold from age 20 to 80. Further, with chronic dosing, highly lipophilic benzodiazepines may require additional attention in geriatric patients. In a study that included individuals up to age 78, steady-state plasma concentrations of diazepam and its metabolite, desmethyldiazepam (DMDZ), were 30% to 35% higher in older patients compared to younger individuals.52 In this study, the half-lives for the young and older patients were 31 hours and 86 hours, respectively, for diazepam, and 40 hours and 80 hours, respectively, for the active metabolite. The half-life of diazepam is increased by “1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age, as the volume of distribution is increased, and clearance is decreased.”52 Clinically, this implies that in older adults, clinicians should expect lower peak concentrations (Cmax), higher trough concentrations (Cmin), and that diazepam will take longer to reach steady-state concentrations. Taken together, these findings raised concern that “slow accumulation and delayed washout of diazepam and DMDZ is probable.”52 These findings—which may have more clinical relevance than those of single-dose studies—suggest that the effects related to diazepam would also take longer to resolve in older patients. Finally, lorazepam clearance or distribution does not appear to be affected by aging, at least in patients age 15 to 73.40 Alprazolam is more slowly cleared in geriatric patients and its effects may be potentiated by reduced protein binding.
Continue to: Obesity
Obesity
The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.55,56
Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.57 Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.58 However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In
How quickly do benzodiazepines work?
Benzodiazepines act quickly. Meta-analyses36 suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 336). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psychotherapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.
What is the ‘best’ dose?
As seen with other classes of psychotropic medications,4 the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).36 A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.49 As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.62 This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.63 As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.
Which benzodiazepine should I prescribe?
Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al36 that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 436).
Continue to: Another aspect of the superiority...
Another aspect of the superiority of clonazepam in some research relates to its pharmacokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.64 While it is difficult to assess this in clinical trials, Herman et al65 provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.
Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.
Practical considerations
When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.
Patients age <18 are unlikely to have full expression of GABA receptors in the brain30 and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzodiazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, some benzodiazepines may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of some oral benzodiazepines is also accelerated, potentially decreasing half-life by up to 50%.
When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.
Continue to: The properties of individual benzodiazepines...
The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.
Bottom Line
The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.
Related Resources
- Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
- Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.
Drug Brand Names
Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan
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60. Abernethy DR, Greenblatt DJ, Divoll M, et al. Prolonged accumulation of diazepam in obesity. J Clin Pharmacol. 1983;23(8-9):369-376. doi:10.1002/j.1552-4604.1983.tb02750.x
61. Abernethy DR, Greenblatt DJ, Divoll M, et al. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873-880.
62. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry. 1993;54 Suppl:4-11.
63. Chen YT, Liu CY, Chang CM, et al. Perceptions, clinical characteristics, and other factors associated with prolonged and high daily dose of benzodiazepine use among patients with anxiety or depressive disorders. J Affect Disord. 2020;271:215-223. doi:10.1016/j.jad.2020.03.077
64. Herman JB, Brotman AW, Rosenbaum JF. Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry. 1987;48(Suppl):22-28.
65. Herman JB, Rosenbaum JF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol. 1987;7(3):175-178.
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